TNF and receptor superfamily members thereof play an important role in the body in various processes such as defenses, inflammation response, immune regulation and so on. They function through paracrine, autocrine and endocrine in a membrane-bound or soluble form. When they bind to the corresponding receptor, a series of biological effects can be caused.
TNF family receptors typically are type I transmembrane proteins and composed of several extracellular region enriched with cysteine domain (CRD) and an intracellular region comprising TRAF protein connection site, wherein the intracellular region also contains a death domain in some cases.
Human transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) belongs to TNFR superfamily and is a type III membrane protein having 293 amino acid residues (166 residues in extracellular domain, 10 residues in transmembrane domain and 117 residues in intracellular function domains), wherein there is no signal peptide in amino-terminal. There are two cysteine-rich repeat regions (S33-66 and C70-C104) in extracellular domain, lacking the “death domain” of TNF family compared to other TNF receptor superfamily members. TACI is mainly expressed on B cells and activated T cells, regulates T-cell non-dependent B-cell antibody response, type transformation and B cell homeostasis, and may have a more important role in the transduction of negative signal.
B lymphocyte stimulator factor (BAFF, also known as BLyS, THANK, zTNF-4, TALL-1 and TNFSF-13B) and A proliferation-inducing factor (APRIL, also known as TALL-2, TRDL-1 and TNFSF-13) are newly discovered two members in TNF ligand superfamily having close relationship and directly related to the development of B lymphocytes, T-cell activation and humoral immunity. The overexpression of BAFF and APRIL may be involved in the production of autoreactive B cell and destruction of autoimmune tolerance, thereby affecting immune response and leading to various autoimmune diseases and malignancies. BAFF can bind to the receptor BCMA (B cell maturation antigen), TACI (TNFR homology transmembrane activator and calcium modulator and cyclophilin ligand interactor) and Hekou BAFF-R (BAFF receptor, BR3), wherein these three receptors are type III transmembrane proteins belonging to TNFR superfamily, and BCMA and TACI are also receptors of APRIL.
TACI is a receptor for both BAFF and APRIL and can recognize BAFF and acts on APPIL. In addition, BAFF/APRRIL heterologous trimer seems to be recognized by TACI.
BAFF/APPRIL, as an important immune regulatory molecule, plays a key role in the maintenance of B cell homeostasis.
BAFF has a strong B cell chemotaxis, can induce activated B cells to secrete large amounts of immunoglobulins such as IgG, IgA, and IgM, etc. to enhance the humoral immune response and can act as a co-stimulating factor regulating T cell activation and response. In the body, it can promote the development of T1-B cells in the spleen into T2-B cells and mature B cells. The overexpression of BAFF may be involved in generation of autoreactive B cells and damage of autoimmune tolerance, i.e., BAFF signal change affects the humoral immune response, thereby resulting in an autoimmune disease or cancer.
The studies have showed that BAFF/APPRIL level is significantly increased in the body of patients suffering autoimmune diseases such as in the serum of patients with systemic lupus erythematosus and the titer of anti-dsDNA antibody thereof is positively correlated. In rheumatoid arthritis patients, serum BAFF/APPRIL level is significantly increased.
Since BAFF/APPRIL overexpression is closely associated with the autoimmune disease, blocking activity of BAFF/APPRIL as a target molecule can reduce the incidence of the disease and reduce the disease symptoms so as to achieve the purpose of mitigation and treatment of autoimmune diseases. The antibodies and corresponding receptors which block BAFF/APPRIL signal can specifically affect the target cells and therefore are potential biological preparation for treating an autoimmune disease.
Therefore, there is an urgent need in the art to develop new compounds which can effectively inhibit or block BAFF/APPRIL pathway.